: Orlistat, a lipase inhibitor taken with meals at doses of 60 mg (available over-the-counter) or 120 mg (prescription only) for treatment of obesity, is known to impair the absorption of fat-soluble molecules. Dalcetrapib, a modulator of cholesteryl ester transfer protein activity, is a lipophilic thioester prodrug. Lipase-induced and pancreatin-induced hydrolysis of dalcetrapib in biorelevant media in vitro was very efficiently inhibited by orlistat. Thus, the potential for orlistat to affect the bioavailability of concomitantly administered dalcetrapib was studied in an open-label 2-cohort study in 24 healthy volunteers as follows: single 600-mg doses of dalcetrapib were administered with increasing doses of orlistat (cohort A: 10, 40, 120 mg; cohort B: 20, 60, 120 mg). Exposure to the active form of dalcetrapib was more than 50% lower when taken with orlistat 60 mg or 120 mg than when taken alone. Similar trends were observed with lower orlistat doses (20 mg and 40 mg). Concomitant administration of orlistat also reduced the pharmacodynamic effects of dalcetrapib treatment on cholesteryl ester transfer protein activity. The interaction exceeds that predicted on the basis of dalcetrapib lipophilicity. These findings demonstrate the potential for large interactions between orlistat and esters that undergo de-esterification in the gastrointestinal tract, independent of lipophilicity.

These results indicate no clinically relevant interactions for co-administration of dalcetrapib with atorvastatin.

No abstract

In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/ morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.

Co-administration of aleglitazar with a statin does not alter the pharmacokinetic profile of either drug.